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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Ahlqvist E, Storm P, Käräjämäki A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol 2018; published online Feb 28.

2 Clustering of adult-onset diabetes into novel subgroups guides therapy and improves projection of outcome TABLE OF CONTENTS... 1 Supplementary figures... 2 Figure S1. Results of sex-specific TwoStep clustering in ANDIS Figure S2. Results of sex-specific k-means clustering in ANDIS... 3 Figure S3. Replication of clustering in two independent Swedish cohorts, SDR and ANDIU Figure S4. Clustering in DIREVA comparing patients with newly diagnosed diabetes and longer duration Figure S5. Prevalence of ketoacidosis at diagnosis in ANDIS Figure S6. Prevalence of non-alcoholic fatty liver disease (NAFLD) in ANDIS... 6 Figure S7. Auto-antibodies directed against zinc transporter 8A (ZnT8A) Figure S8. Antidiabetic medication at time of registration in ANDIS Figure S9. Metformin treatment by cluster in ANDIS... 7 Figure S10. Risk of diabetic complications by cluster Figure S11. Diabetic retinopathy at diagnosis... 9 Figure S12. Prevalence of chronic kidney disease in DIREVA Figure S13. Change in cluster variables over time in ANDIS Supplementary tables Table S1. Patient characteristics in ANDIS using the traditional classification Table S2. Patient characteristics in ANDIS using k-means clustering Table S3. Cluster center coordinates in ANDIS Table S4. Classifier performance for cluster assignment based on Euclidian distance to ANDIS cluster centers Table S5. Logistic regression analysis of risk factors for ketoacidosis at diagnosis in ANDIS Table S6a. Cox regression analysis comparing antidiabetic treatments between clusters in ANDIS Table S6b. Pairwise comparisons of cox-regressions in table 6a Table S7a. Cox regression analysis comparing risk of kidney complications in ANDIS Table S7b. Pairwise comparisons of cox-regressions adjusted for sex and age at onset of diabetes Table S7c. Pairwise comparisons of cox-regressions adj. for sex, age at diabetes onset and first egfr Table S8a. Cox regression analysis comparing risk of cardiovascular disease between clusters in ANDIS Table S8b. Pairwise comparisons of cox-regressions in table 8a adjusted for sex Table S8c. Pairwise comparisons of cox-regressions in table 8a adjusted for sex and age Table S9a. Cox regression analysis comparing risk of kidney complications between clusters in SDR Table S9b. Pairwise comparisons of cox-regressions in table 9a adjusted for sex and age at onset Table S9c. Pairwise comparisons of cox-regressions in table 9a adj. for sex, age at onset, first egfr Table S10a. Cox regression analysis comparing risk of diabetic retinopathy between clusters in SDR Table S10b. Pairwise comparisons of cox-regressions in table 10a Table S11a. Cox regression analysis comparing risk of cardiovascular disease between clusters in SDR Table S11b. Pairwise comparisons of cox-regressions in table 11a adjusted for sex Table S11c. Pairwise comparisons of cox-regressions in table 11a adj. for sex, age at onset Table S12. Strongest genetic associations with specific ANDIS clusters Table S13. SNPs included in genetic risk scores Table S14. Genetic risk score analysis

3 Supplementary figures A B C D Figure S1. Results of sex-specific TwoStep clustering in ANDIS. The distribution of patients based on TwoStep cluster analysis in the ANDIS (All New Diabetes in Scania) cohort was similar in (A) men and (B) women. The different clusters in men (C) and women (D) had similar distribution of the variables used for clustering, i.e. of HAa1c (mmol/mol) at diagnosis; BMI (kg/m 2 ), age (years), HOMA2-B (%) and HOMA2-IR at registration, except for some differences in clusters 3 and 4 (women in cluster 4 were older and less obese compared to men in cluster 3).

4 A B C D Figure S2. Results of sex-specific k-means clustering in ANDIS. The distribution of patients based on k-means cluster analysis in ANDIS was similar in men (A) and women (B). The different clusters in men (C) and women (D) had similar distribution of the variables used for clustering, i.e. of Hba1c (mmol/mol) at diagnosis; BMI (kg/m 2 ), age (years), HOMA2-B (%) and HOMA2-IR at registration.

5 A B C D E Figure S3. Replication of clustering in two independent Swedish cohorts, SDR and ANDIU. Cluster distributions and characteristics in the Scania Diabetes Registry (SDR) using TwoStep (A), k- means (k=4) clustering (B) and cluster assignment based on ANDIS cluster coordinates (C). Cluster distributions and characteristics in ANDIU using k- means (k=4) clustering (D) and cluster assignment based on ANDIS cluster coordinates (E).

6 A B C D Figure S4. Clustering in the Finnish DIREVA cohort comparing patients with newly diagnosed diabetes and longer duration. Patient distribution in DIREVA in newly diagnosed (diabetes duration at sampling less than 2 years) using de novo k- means clustering (A), and cluster assignment based on ANDIS cluster coordinates (B). Patient distribution in patients with longer duration at sampling (mean 10 15±10 34 years) using de novo k-means clustering (C) and cluster assignment based on ANDIS cluster coordinates (D).

7 Figure S5. Prevalence of ketoacidosis at diagnosis in ANDIS. Ketoacidosis at diagnosis was most common in clusters 1/SAID (124 of 406; 30 5%) and 2/SIDD (259 of 1033;25 1%), but only occurred in 23 of 842 SIRD patients, 56 of 1215 of MOD patients and 38 of 2273 MARD patients. Figure S6. Prevalence of non-alcoholic fatty liver disease (NAFLD) in ANDIS estimated from ALT measurements. A total of patients had at least one P-ALT measurement in the database of the Clinical Chemistry unit. Of them, 3739 had at least two readings exceeding the upper reference values for the assays used (> µkat/l for men and > µkat/l for women). Cluster 3/SIRD had the highest prevalence of NAFLD (302 of 1556; 24 1%), defined as two pathological ALT measurements and BMI>28 (OR 3 96[ ], p=5 8x10-46 compared to MARD (226 of 3415; 7 1%) and OR 1 56[ ], p=1 4x10-4 compared to MOD (381 of 2120; 21.9%) after adjustment for sex and age). Figure S7. Prevalence of auto-antibodies directed against zinc transporter 8A (ZnT8A). ZnT8A auto-antibody positivity was mainly observed in patients from cluster 1/SAID (79 of 289 positive; 27 3%). OR 52 74[ ], p=8 6x10-31 compared to MARD (10 of 1412 positive). Importantly only 9 of 685 (1 3%) SIDD patients were positive.

8 Figure S8. Antidiabetic medication (%) at time of registration in ANDIS. Figure S8 shows the frequency of use of at least metformin, at least insulin or both at registration in ANDIS (at the time of measurement of plasma glucose and C-peptide) stratified by cluster. More patients in cluster 2/SIDD had been prescribed insulin and/or metformin than in clusters 3-5, reflecting the higher HbA1c at diagnosis. Figure S9. Metformin treatment (%) by cluster in ANDIS. The percentage of patients in each cluster prescribed metformin as their first treatment after diagnosis (initial treatment), and percent of renally sufficient (egfr>60 ml/min/1 73m 2 ) patients on metformin at registration. This shows that the difference between clusters is not a result of discontinuation of metformin due to adverse effects or contra-indication of metformin in patients with kidney disease.

9 Figure S10. Risk of diabetic complications by cluster. Cox regressions of diabetic complications for (A) CKD stage 3A (egfr <60 ml/min) in ANDIS and macroalbuminuria (B) in SDR, coronary events (C) and stroke (D) in SDR. Tables show number of individuals at risk. For statistics see Table S7 and S11.

10 A B Figure S11. Diabetic retinopathy (DR) at diagnosis. Prevalence of different stages of diabetic retinopathy in (A) ANDIS and (B) ANDIU. In ANDIS DR risk was significantly higher in SIDD than in the reference cluster MARD (OR 1 6[ ], p=9 7x10-7 ). In ANDIU DR risk was elevated in both SIDD (OR 4 6[ ], p=4 1x10-13 ) and MOD compared to MARD (OR 2 2[ ], p=2 8x10-4 ). Figure S12. Prevalence of chronic kidney disease in DIREVA. CKD (egfr<60 ml/min) in DIREVA by clusters assigned based on ANDIS cluster coordinates. SIRD had increased risk of CKD (OR 2 02[ ], p=3 4x10-4 ) after adjustment for age, sex and duration of diabetes. Median follow-up time was 8 53 years (IQR ).

11 A B Figure S13. Change in cluster variables over time in ANDIS. Figure S13 shows change in BMI (A) and C-peptide (B) during follow-up by cluster.

12 Supplementary tables Table S1. Patient characteristics in ANDIS using the traditional classification.* T1D LADA T2D N Frequency in total cohort, % Men, % Hba1c at diagnosis, mmol/l (27 06) 73 65(28 26) 62 32(24 12) BMI, kg/m (3 50) 28 77(6 32) 30 93(5 72) Age at diagnosis, years 34 03(13 84) 54 86(12 67) 60 93(12 25) HOMA2-B 23 50(20 94) 65 46(46 88) 91 95(48 19) HOMA2-IR 0 66(0 35) 2 64(2 08) 3 41(2 55) Insulin at registration, % Metformin at registration, % History of gestational diabetes, % of women Non-Scandinavian origin, % *Only patients older than 18 at registration are included. Table S2. Patient characteristics in ANDIS using k-means clustering. SAID SIDD SIRD MOD MARD N Frequency, % Men, % Hba1c at diagnosis, mmol/l 80 03(30 84) (19 26) 54 07(15 46) 57 70(16 07) 50 08(9 85) BMI, kg/m (6 44) 28 86(4 77) 33 85(5 24) 35 71(5 43) 27 94(3 44) Age at diagnosis, years 50 48(17 93) 56 74(11 14) 65 25(9 34) 48 96(9 54) 67 37(8 55) HOMA2-B 56 71(44 65) 47 64(28 93) (47 20) 95 03(32 45) 86 59(26 37) HOMA2-IR 2 16(1 56) 3 18(1 73) 5 54(2 74) 3 35(1 21) 2 55(0 84) Insulin at registration, % Metformin at registration, % Family history of diabetes, % History of gestational diabetes, % of women Non-Scandinavian origin, %

13 Table S3. Cluster center coordinates in ANDIS. Cluster Hba1c BMI Age at onset HOMA2-B HOMA2-IR Women 2/SIDD /SIRD /MOD /MARD Men 2/SIDD /SIRD /MOD /MARD Table S4. Classifier performance for cluster assignment based on Euclidian distance to ANDIS cluster centers. Cluster Sensitivity Specificity ANDIU SIDD SIRD MOD MARD SDR SIDD SIRD MOD MARD DIREVA short duration SIDD SIRD MOD MARD DIREVA long duration SIDD SIRD MOD MARD Table S5. Logistic regression analysis of risk factors for ketoacidosis at diagnosis in ANDIS. OR(CI95%)* P HOMA2-B 0 66( ) 1 1x10-7 HOMA2-IR 0 95( ) Age at onset 0 65( ) 1 5x10-17 BMI 0 94( ) HbA1c 2 73( ) 2 0x10-82 *OR are for 1 SD change in variable.

14 Table S6a. Cox regression analysis comparing antidiabetic treatments between clusters in ANDIS. Events Censored % events HR(CI95%) P Sustained insulin 1/SAID ( ) 4 3x /SIDD ( ) 2 5x /SIRD ( ) 7 0x10-6 4/MOD ( ) 1 0x10-5 5/MARD Metformin 1/SAID ( ) /SIDD ( ) 2 7x /SIRD ( ) 8 5x10-5 4/MOD ( ) 1 8x /MARD Oral treatment other than metformin 1/SAID ( ) /SIDD ( ) 3 0x /SIRD ( ) 1 1x /MOD ( ) 2 1x /MARD Reaching treatment goal 1/SAID ( ) 5 5x /SIDD ( ) 1 3x /SIRD ( ) /MOD ( ) 1 3x /MARD The table information from the Swedish Drug Prescription Registry of patient's pick-up of medication from the pharmacy. Sustained insulin is defined as more than 6 months on insulin treatment. Reaching treatment goal is defined as the first time point after diagnosis the HbA1c is below 52 mmol/mol. Table S6b. P-values for pairwise comparisons of cox-regressions in table 6a. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD Sustained insulin <0 0001* <0 0001* <0 0001* <0 0001* <0 0001* <0 0001* Metformin <0 0001* <0 0001* <0 0001* * <0 0001* <0 0001* Oral treatment other than metformin <0 0001* * <0 0001* <0 0001* <0 0001* Reaching treatment goal <0 0001* <0 0001* <0 0001* <0 0001* <0 0001* <0 0001* *Significant after adjustment for multiple comparisons (10 tests).

15 Table S7a. Cox regression analysis comparing risk of kidney complications in ANDIS. Events Censored Events (%) HR(CI95%) 1 p 1 HR(CI95%) 2 p 2 CKD 3A 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 1 4x ( ) 6 4x10-9 4/MOD ( ) ( ) /MARD CKD 3B 1/SAID ( ) ( ) Macroalbuminuria 2/SIDD ( ) ( ) /SIRD ( ) 8 3x ( ) 3 0x10-6 4/MOD ( ) ( ) /MARD /SAID ( ) ( ) /SIDD ( ) 3 7x ( ) 9 0x10-6 3/SIRD ( ) 3 4x ( ) 2 2x10-5 4/MOD ( ) ( ) /MARD ESRD 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 3 8x ( ) /MOD ( ) ( ) /MARD Cox regressions adjusted for sex and age at onset. 2 Cox regression adjusted for sex, age at onset and first egfr. CKD3A was defined as egfr <60 ml/min/1 73m 2 and CKD3B as egfr <45 ml/min/1 73m 2 for more than 90 days. End-stage renal disease (ESRD) was defined as at least one egfr below 15 ml/min/1 73m 2. Macroalbuminuria was defined as at least two out of three consecutive visits with albumin excretion rate (AER) 200 µg/min or AER 300 mg/24 h or albumin-creatinine ratio (ACR) 25/35 mg/mmol for men/women. Median duration at first egfr 53(IQR 1-286) days.

16 Table S7b. P-values for pairwise comparisons of cox-regressions in table 7a adjusted for sex and age at onset of diabetes. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD CKD 3A <0 0001* <0 0001* <0 0001* CKD 3B * * Macroalbuminuria ESRD *Significant after adjustment for multiple comparisons (10 tests). Table S7c. P-values for pairwise comparisons of cox-regressions in table 7a adjusted for sex, age at onset of diabetes and first egfr. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD CKD 3A * CKD 3B Macroalbuminuria ESRD *Significant after adjustment for multiple comparisons (10 tests).

17 Table S8a. Cox regression analysis comparing risk of cardiovascular disease between clusters in ANDIS. CE Stroke Events Censored Events (%) HR(CI95%) 1 p 1 HR(CI95%) 2 p 2 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 1 2x ( ) /MOD ( ) ( ) /MARD /SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) ( ) /MOD ( ) 9 0x ( ) /MARD Cox regression adjusted for sex. 2 Cox regressions adjusted for sex and age at onset. Coronary events (CE) were defined by ICD-10 codes I21, I20, I251, I253, I254, I255, I256, I257, I258, I259. Stroke was defined by ICD-10 codes I60, I61, I63 and I64. Table S8b. P-values for post hoc pairwise comparisons of cox-regressions in table 8a adjusted for sex. CE Stroke SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD * * <0 0001* <0 0001* <0 0001* *Significant after adjustment for multiple comparisons (10 tests). Table S8c. P-values for post hoc pairwise comparisons of cox-regressions in table 8a adjusted for sex and age. CE Stroke SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD *Significant after adjustment for multiple comparisons (10 tests).

18 Table S9a. Cox regression analysis comparing risk of kidney complications between clusters in SDR. Events Censored Events (%) HR(CI95%) 1 p 1 HR(CI95%) 2 p 2 CKD 3A 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 2 4x ( ) /MOD ( ) ( ) /MARD CKD 3B 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 3 0x ( ) /MOD ( ) ( ) /MARD Macroalbuminuria 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) ( ) /MOD ( ) ( ) /MARD ESRD 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 2 4x ( ) 3 9x10-5 4/MOD ( ) ( ) /MARD Cox regressions adjusted for sex and age at onset. 2 Cox regression adjusted for sex age at onset and first egfr. CKD3A was defined as egfr < 60 ml/min/1 73m 2 and (CKD 3B) as egfr < 45 ml/min/1 73m 2 for more than 90 days. End-stage renal disease (ESRD) was defined as at least one egfr below 15 ml/min/1 73m 2. Macroalbuminuria was defined as at least two out of three consecutive visits with albumin excretion rate (AER) 200 µg/min or AER 300 mg/24 h or albumin-creatinine ratio (ACR) 25/35 mg/mmol for men/women. Median duration at first egfr=100(iqr ) days. Table S9b. P-values for pairwise comparisons of cox-regressions in table 9a adjusted for sex and age at onset. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD CKD 3A CKD 3B Macroalbuminuria ESRD

19 Table S9c. P-values for pairwise comparisons of cox-regressions in table 9a adjusted for sex, age at onset and first egfr. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD CKD 3A CKD 3B Macroalbuminuria * ESRD *Significant after adjustment for multiple comparisons (10 tests). Table S10a. Cox regression analysis comparing risk of diabetic retinopathy between clusters in SDR. Cluster Events Censored Events (%) HR(CI95%) 1 p 1 HR(CI95%) 2 p 2 DR 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) ( ) /MOD ( ) ( ) /MARD Cox regressions adjusted for sex. 2 Cox regression adjusted for sex and age at onset. Table S10b. P-values for post hoc pairwise comparisons of cox-regressions in table 10a. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD DR * * DR <0 0001* * 1 Cox regressions adjusted for sex. 2 Cox regression adjusted for sex and age at onset. *Significant after adjustment for multiple comparisons (10 tests).

20 Table S11a. Cox regression analysis comparing risk of cardiovascular disease between clusters in SDR. Cluster Events Censored Events (%) HR(CI95%) 1 p 1 HR(CI95%) 2 p 2 CE 1/SAID ( ) ( ) /SIDD ( ) ( ) /SIRD ( ) 1 5x ( ) /MOD ( ) ( ) /MARD Stroke 1/SAID ( ) ( /SIDD ( ) ( ) /SIRD ( ) ( ) /MOD ( ) ( ) /MARD Cox regression adjusted for sex. 2 Cox regressions adjusted for sex and age at onset. Coronary events (CE) were defined by ICD-10 codes I21, I20, I251, I253, I254, I255, I256, I257, I258, I259. Stroke was defined by ICD-10 codes I60, I61, I63. Table S11b. P-values for post hoc pairwise comparisons of cox-regressions in table 11a adjusted for sex. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD CE * <0 0001* Stroke *Significant after adjustment for multiple comparisons (10 tests). Table S11c. P-values for post hoc pairwise comparisons of cox-regressions in table 11a adjusted for sex and age at onset. SAID vs SIDD SAID vs SIRD SAID vs MOD SIDD vs SIRD SIDD vs MOD SIRD vs MOD CE Stroke *Significant after adjustment for multiple comparisons (10 tests).

21 Table S12. Strongest genetic associations with specific ANDIS clusters (reaching p<0.01). SNP Candidate gene SAID SIDD SIRD MOD MARD Difference cluster 2-5 N=313 N=676 N=603 N=727 N=1646 MAF OR P OR P OR P OR P OR P P rs HLA_DQB ( ) 5 7x ( ) ( ) ( ) ( ) rs GCC1-PAX ( ) 7 8x ( ) ( ) ( ) ( ) 4 2x rs IRS ( ) ( ) ( ) ( ) ( ) rs LAMA ( ) ( ) ( ) ( ) ( ) rs WFS ( ) ( ) ( ) ( ) ( ) rs TCF7L ( ) ( ) 2 8x ( ) ( ) 5 7x ( ) 1 1x x10-6 rs TM6SF ( ) ( ) ( ) 3 1x ( ) ( ) rs IGF2BP ( ) ( ) ( ) ( ) ( ) 2 1x rs CDKN2B ( ) ( ) ( ) ( ) ( ) rs BCL11A ( ) ( ) ( ) ( ) ( ) rs HHEX/IDE ( ) ( ) ( ) ( ) ( ) rs COBL ( ) ( ) ( ) ( ) ( ) rs SFRS ( ) ( ) ( ) ( ) ( ) rs5219 KCNJ ( ) ( ) ( ) ( ) ( ) rs JAZF ( ) ( ) ( ) ( ) ( ) rs BCAR ( ) ( ) ( ) ( ) ( ) rs ADCY ( ) ( ) ( ) ( ) ( ) 1 5x rs ANK ( ) ( ) ( ) ( ) ( ) rs BCL11A ( ) ( ) ( ) ( ) ( ) rs CCND ( ) ( ) ( ) ( ) ( ) rs PROX ( ) ( ) ( ) ( ) ( ) Maximum likelihood estimation using geographically matched non-diabetic controls (N=2754). 20

22 Table S13. SNPs included in genetic risk scores. SNP Effect allele Weight Chr location Locus Insulin resistance rs G ANKRD55 intergenic rs C GRB14 intergenic rs C IRS1 intergenic rs A MC4R intergenic rs C PPARG coding - missense Insulin secretion rs G CDKN2B intergenic rs G MTNR1B intron rs T HHEX/IDE intergenic rs A ADCY5 intron rs G SLC30A8 coding - missense rs A CENTD2 intergenic rs G KCNQ1 intron rs T DGKB intergenic rs T DGKB/TMEM195 intergenic rs T IGF2BP2 intron rs A GCK intergenic rs5219 T KCNJ11 coding - missense rs T G6PC2/ABCB11 intron rs A GLIS3 intron rs G CDKAL1 intron rs T TCF7L2 intron / promoter T2D rs G WFS1 intron rs C SUGP1/CILP2 intron rs A GIPR intron rs T CDKN2B intergenic rs C KLHDC5 intergenic rs G ADRA2A intergenic rs T NOTCH2 intron rs G CCND2 intergenic rs A FAM148B intergenic rs C HHEX/IDE intergenic rs A DCD intergenic rs A CRY2 intron rs G ZFAND6 intergenic rs A ADCY5 intron rs A ZMIZ1 intron rs G CDC123/CAMK1D intergenic rs C SLC30A8 coding - missense rs C HMGA2 intron of pseudogene rs A CENTD2 intergenic 21

23 rs G KCNQ1 intron rs T DGKB intergenic rs T FADS1 intron rs C MC4R intergenic rs C PPARG coding - missense rs G MACF1 coding - missense rs G KCNQ1 intron rs T BCL11A intergenic rs G TLE1 intergenic rs C IRS1 intergenic rs C PROX1 intergenic rs35767 G IGF1 neargene-5 rs A GRB14 intergenic rs T IGF2BP2 intron rs G ZBED3 intron of ZBED3-AS1 rs G ANKRD55 intergenic rs C ADAMTS9-AS2 intron rs A GCK intergenic rs C ANK1 intron rs5219 C KCNJ11 coding - missense rs A ADRA2A UTR-3 rs T G6PC2/ABCB11 intron rs G FITM2/R3HDML/HNF4A intergenic rs G GCC1-PAX4 intergenic rs C MAEA intron rs A GLIS3 intron rs A BCDIN3D/FAIM2 intergenic rs G HMG20A intergenic rs T BCAR1 intergenic rs T THADA coding - missense rs C RBMS1/ITGB6 intron rs T COBLL1 coding - missense rs C CDKAL1 intron rs G CDKAL1 intron rs T TCF7L2 intron / promoter rs G MADD intron rs T OASL/TCF1/HNF1A intron of OASL rs C TSPAN/LGR5 intergenic rs A PRC1 intron rs G LAMA1 intron rs G GIPR intergenic rs C PSMD6 intergenic rs T JAZF1 intron rs T TP53INP1 intron rs C ZFAND3 intron

24 Table S14. Genetic risk score analysis. T2D Insulin secretion Insulin resistance OR P OR P OR P SAID 1 22( ) ( ) ( ) SIDD 1 45( ) 7 3x ( ) ( ) SIRD 1 07( ) ( ) ( ) MOD 1 28( ) 4 6x ( ) ( ) MARD 1 44( ) 3 0x ( ) 1 0x ( ) OR are for 1 SD change in genetic risk score.

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